19-43612276-C-T

Variant names:

• chr19-43612276-C-T
• rs552275462
• NM_001145641.2:c.155C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001145641.2(SRRM5):​c.155C>T​(p.Ser52Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000715 in 1,399,436 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S52C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: SRRM5 NM_001145641.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.501
• Publications: 0 publications found

Genes affected

SRRM5 (HGNC:37248): (serine/arginine repetitive matrix 5)

ZNF428 (HGNC:20804): (zinc finger protein 428) Predicted to enable metal ion binding activity. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14143232).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001145641.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SRRM5	NM_001145641.2	MANE Select	c.155C>T	p.Ser52Phe	missense	Exon 1 of 1	NP_001139113.1	B3KS81
	ZNF428	NM_182498.4	MANE Select	c.76+1953G>A		intron	N/A	NP_872304.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SRRM5	ENST00000417606.3	TSL:6 MANE Select	c.155C>T	p.Ser52Phe	missense	Exon 1 of 1	ENSP00000414512.1	B3KS81
	ZNF428	ENST00000300811.8	TSL:1 MANE Select	c.76+1953G>A		intron	N/A	ENSP00000300811.2	Q96B54
	SRRM5	ENST00000607544.1	TSL:2	c.155C>T	p.Ser52Phe	missense	Exon 3 of 3	ENSP00000476253.1	B3KS81

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.15e-7 AC: 1 AN: 1399436 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 690234

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 31598

American (AMR) AF: 0.00 AC: 0 AN: 35704

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25182

East Asian (EAS) AF: 0.00 AC: 0 AN: 35738

South Asian (SAS) AF: 0.00 AC: 0 AN: 79236

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49294

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5698

European-Non Finnish (NFE) AF: 9.27e-7 AC: 1 AN: 1078974

Other (OTH) AF: 0.00 AC: 0 AN: 58012

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	15
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0024	T
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.50
FATHMM_MKL	Benign	0.041	N
LIST_S2	Benign	0.49	T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.50
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.49	N
REVEL	Benign	0.064
Sift	Uncertain	0.026	D
Sift4G	Benign	0.14	T
Polyphen		0.97	D
Vest4		0.080
MutPred		0.23		Loss of phosphorylation at S52 (P = 0.0035)
MVP		0.061
MPC		0.051
ClinPred		0.40	T
GERP RS		2.4
PromoterAI		-0.0018	Neutral
Varity_R		0.046
gMVP		0.028
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs552275462; hg19: chr19-44116428;